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FTR #1166 Bio-Psy-Op Apocalypse Now, Part 22: A Pound of Cure, Part 1

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FTR #1166 This pro­gram was record­ed in one, 60-minute seg­ment.

Intro­duc­tion: Sup­ple­ment­ing FTR #1138, this pro­gram con­tin­ues dis­cus­sion about drug treat­ments for, and vac­cines to pre­vent, Covid-19.

In pre­vi­ous posts and pro­grams, we have not­ed that Mod­er­na’s vac­cine work has been financed by DARPA. We have also not­ed that the over­all head of Oper­a­tion Warp Speed is Mon­cef Slaoui, for­mer­ly in charge of prod­uct devel­op­ment for Mod­er­na!

Of great sig­nif­i­cance is the cen­tral role of the mil­i­tary in the devel­op­ment of treat­ment for Covid-19:

  1. The pro­gram notes that: ” . . . . Remde­sivir pre­dates this pan­dem­ic. It was first con­sid­ered as a poten­tial treat­ment for Ebo­la, and was devel­oped through a long­stand­ing part­ner­ship between the U.S. Army and the Cen­ters for Dis­ease Con­trol and Pre­ven­tion. . . .”
  2. Jonathan King, who has chaired the micro­bial phys­i­ol­o­gy study sec­tion for the NIH has sound­ed the alarm about “vac­cine research” mask­ing offen­sive bio­log­i­cal war­fare research: “. . . . King, who has chaired the micro­bial phys­i­ol­o­gy study sec­tion for the NIH, believes that with­out inten­sive inde­pen­dent scruti­ny, the Pen­ta­gon is free to obscure its true goals. ‘The Defense Depart­ment appears to be pur­su­ing many nar­row, applied goals that are by nature offen­sive, such as the genet­ic ‘improve­ment’ of BW agents,’ King says. ‘But to achieve polit­i­cal accept­abil­i­ty, they mask these inten­tions under forms of research, such as vac­cine devel­op­ment, which sound defen­sive. . . .”
  3. Mod­er­na’s vac­cine devel­op­ment was over­seen by an unnamed Pen­ta­gon offi­cial: ” . . . . Moderna’s team was head­ed by a Defense Depart­ment offi­cial whom com­pa­ny exec­u­tives described only as ‘the major,’ say­ing they don’t know if his name is sup­posed to be a secret. . . . .”
  4. The per­va­sive role of the mil­i­tary in Oper­a­tion Warp Speed (the Trump admin­is­tra­tion’s vac­cine devel­op­ment pro­gram) has gen­er­at­ed alarm in civil­ian par­tic­i­pants:”. . . . Scores of Defense Depart­ment employ­ees are laced through the gov­ern­ment offices involved in the effort, mak­ing up a large por­tion of the fed­er­al per­son­nel devot­ed to the effort.  Those num­bers have led some cur­rent and for­mer offi­cials at the Cen­ters for Dis­ease Con­trol and Pre­ven­tion to pri­vate­ly grum­ble that the military’s role in Oper­a­tion Warp Speed was too large for a task that is, at its core, a pub­lic health cam­paign. . . .
  5. Gen­er­al Gus­tave Perna–one of the prin­ci­pals in Oper­a­tion Warp Speed–has cho­sen a retired Lieu­tenant Gen­er­al to over­see much of the pro­gram: ” . . . . ‘Frankly, it has been breath­tak­ing to watch,’ said Paul Ostrows­ki, the direc­tor of sup­ply, pro­duc­tion and dis­tri­b­u­tion for Oper­a­tion Warp Speed. He is a retired Army lieu­tenant gen­er­al who was select­ed to man­age logis­tics for the pro­gram by Gen. Gus­tave F. Per­na, the chief oper­at­ing offi­cer for Oper­a­tion Warp Speed. . . .”
  6. The mil­i­tary will be able to trace the des­ti­na­tion and admin­is­tra­tion of each dose: ” . . . . Mil­i­tary offi­cials also came up with the clever idea — if it works — to coor­di­nate the deliv­ery of vac­cines to drug­stores, med­ical cen­ters and oth­er immu­niza­tion sites by send­ing kits full of nee­dles, syringes and alco­hol wipes. Vac­cine mak­ers will be alert­ed when the kits arrive at an immu­niza­tion site so they know to ship dos­es. Once the first dose is giv­en, the man­u­fac­tur­er will be noti­fied so it can send the sec­ond dose with a patient’s name attached sev­er­al weeks lat­er. The mil­i­tary will also mon­i­tor vac­cine dis­tri­b­u­tion through an oper­a­tions cen­ter. ‘They will know where every vac­cine dose is,’ Mr. [Paul] Man­go said on a call with reporters. . . .”

This pro­gram begins with infor­ma­tion about the ongo­ing pro­fes­sion­al mas­sag­ing of Gilead Sci­ences’ anti-viral remde­sivir.

The most pos­i­tive stud­ies have proved remdesivir/Veklury only mod­est­ly suc­cess­ful against SARS Cov‑2 (the virus that caus­es Covid-19). Remde­sivir (now mar­ket­ed under the brand name Vek­lury) has been pro­pelled to the fore­front of treat­ment reg­i­mens for the pan­dem­ic, a devel­op­ment which appears to dimin­ish the chances for a com­pet­ing, more effec­tive drug to gain pro­fes­sion­al approval for treat­ing Covid-19.

” . . . . Oth­er stud­ies have shown no ben­e­fit, includ­ing the World Health Organization’s Sol­i­dar­i­ty tri­al, released as a preprint on Oct. 15. Based on these results, the Euro­pean Soci­ety of Inten­sive Care Med­i­cine is now rec­om­mend­ing that the drug not be rou­tine­ly used in hos­pi­tal­ized Covid-19 patientsInfec­tious dis­ease experts have stat­ed that after exam­in­ing all avail­able evi­dence, we can rea­son­ably con­clude only that remde­sivir may work. . . .”

Deeply dis­turb­ing, as well, is the news that the “pos­i­tive news” about vac­cine suc­cess and devel­op­ment has been gen­er­at­ed by press releas­es from the com­pa­nies that man­u­fac­ture them: ” . . . . But the com­pa­nies announced the find­ings in news releas­es, not in peer-reviewed sci­en­tif­ic jour­nals, and did not dis­close the detailed data that would allow out­side experts to eval­u­ate their claims. There­fore, the results can­not be con­sid­ered con­clu­sive. The fig­ures on effec­tive­ness may change as the stud­ies con­tin­ue. . . .”

Pro­gram High­lights Include: The rapid spread of the dis­ease is ben­e­fit­ting the speed-up of vac­cine research; how reg­u­la­to­ry pro­ce­dures for Big Phar­ma prod­ucts were already being atten­u­at­ed before the Covid-19 “op;” review of the atten­u­at­ed, manip­u­lat­ed NIAID study on remde­sivir that gen­er­at­ed pos­i­tive news, a run-up in the stock price of Gilead Sci­ences and a boost for the mar­ket as a whole; review of the role of “Sci­en­tists to Stop Covid-19” in mas­sag­ing the vet­ting process for remde­sivir; review of the CDC’s clos­ing of the USAMRIID in August of 2019 and the test­ing of remdeisivir at that facil­i­ty in March of 2019; review of the insid­i­ous, inces­tu­ous rela­tion­ship between the author­i­ties “reg­u­lat­ing” treat­ment of Lyme Dis­ease and those who ben­e­fit from the admin­is­tra­tion of that treat­ment; review of Lyme Dis­ease as a bio­log­i­cal war­fare weapon.

1. Expand­ing our cov­er­age of Gilead Sci­ences’ anti-viral remde­sivir, the pro­gram notes that: ” . . . . Remde­sivir pre­dates this pan­dem­ic. It was first con­sid­ered as a poten­tial treat­ment for Ebo­la, and was devel­oped through a long­stand­ing part­ner­ship between the U.S. Army and the Cen­ters for Dis­ease Con­trol and Pre­ven­tion. . . .”

“Does Remde­sivir Work?” by Ravi Gup­ta and Resh­ma Ramachan­dran; The New York Times; 11/18/2020.

When the Food and Drug Admin­is­tra­tion approves a new treat­ment or vac­cine, as doc­tors we are assured that rig­or­ous stud­ies have proven it to be safe and effec­tive. But the F.D.A.’s hap­haz­ard issuance of emer­gency use autho­riza­tions for Covid-19 treat­ments like hydrox­y­chloro­quine and con­va­les­cent plas­ma, whose poten­tial ben­e­fits have not yet been backed up by data, has under­mined this trust.

Ear­ly in the pan­dem­ic, the agency award­ed an emer­gency use autho­riza­tion for the antivi­ral drug remde­sivir, based on evi­dence sug­gest­ing that it may be effec­tive. Then last month, despite con­flict­ing evi­dence, the F.D.A. pre­ma­ture­ly grant­ed its first full approval for Covid-19 treat­ment to remde­sivir, now mar­ket­ed as Vek­lury.

In ear­ly Octo­ber, The New Eng­land Jour­nal of Med­i­cine pub­lished a report on the results of a tri­al fund­ed by the Nation­al Insti­tutes of Health that found that remde­sivir decreased recov­ery time in Covid-19 patients who were hos­pi­tal­ized with less severe ill­ness, but did not curb mor­tal­i­ty. Oth­er stud­ies have shown no ben­e­fit, includ­ing the World Health Organization’s Sol­i­dar­i­ty tri­al, released as a preprint on Oct. 15.

Based on these results, the Euro­pean Soci­ety of Inten­sive Care Med­i­cine is now rec­om­mend­ing that the drug not be rou­tine­ly used in hos­pi­tal­ized Covid-19 patientsInfec­tious dis­ease experts have stat­ed that after exam­in­ing all avail­able evi­dence, we can rea­son­ably con­clude only that remde­sivir may work.

Some have argued that the approval of Vek­lury is jus­ti­fied even if it is only mild­ly effec­tive because there are no oth­er proven ther­a­pies for Covid-19. This fails to acknowl­edge, how­ev­er, the proven effec­tive­ness of drugs like dex­am­etha­sone, a cheap and wide­ly used steroid.

It also ignores years of assault on F.D.A. evi­den­tiary stan­dards, accel­er­at­ed by the pas­sage in 2016 of the 21st-Cen­tu­ry Cures Act. This leg­is­la­tion, which sped up the F.D.A.’s approval process, was based on unfound­ed claims that the agency was too slow and hin­dered patients’ access to life­sav­ing drugs.

The F.D.A. is now increas­ing­ly approv­ing new drugs based on weak­er evi­dence, rely­ing on “sur­ro­gate mea­sures” like changes in tumor size in lieu of more mean­ing­ful clin­i­cal out­comes such as reduced mor­tal­i­ty or hos­pi­tal­iza­tions. Recent can­cer drugs, for exam­ple, have been approved with­out evi­dence of improv­ing over­all sur­vival. Weak­er stan­dards are a boon to phar­ma­ceu­ti­cal com­pa­nies, but they can also depress the devel­op­ment of tru­ly inno­v­a­tive and effec­tive treat­ments.

The F.D.A. has tried to off­set its accel­er­at­ed approval of Vek­lury by ask­ing its mak­er, Gilead, to com­plete 29 post-mar­ket stud­ies to fur­ther exam­ine the drug’s effec­tive­ness and safe­ty. This is more than three to four times the num­ber typ­i­cal­ly request­ed. It’s unclear, how­ev­er, if these stud­ies will ever be done. One report found that, five to six years fol­low­ing approval, only half of post-mar­ket stud­ies had been com­plet­ed and one-fifth hadn’t even been start­ed.

Veklury’s approval could also have a chill­ing effect on the F.D.A.’s abil­i­ty to issue emer­gency use autho­riza­tions for oth­er poten­tial­ly effec­tive Covid-19 treat­ments, as the agency’s guid­ance requires there be “no ade­quate, approved and avail­able alter­na­tive” for the dis­ease. Just last week, the F.D.A. grant­ed an autho­riza­tion to an anti­body treat­ment called bam­lanivimab, for use in non-hos­pi­tal­ized patients with Covid-19 who are at the high­est risk of devel­op­ing severe dis­ease. This may have been pos­si­ble only because Vek­lury was approved specif­i­cal­ly for hos­pi­tal­ized patients.

Veklury’s ques­tion­able effec­tive­ness is even more prob­lem­at­ic giv­en the drug’s price. A course costs $3,120 — a huge price tag, and one that ignores the sub­stan­tial pub­lic invest­ment in the drug’s devel­op­ment.

Remde­sivir pre­dates this pan­dem­ic. It was first con­sid­ered as a poten­tial treat­ment for Ebo­la, and was devel­oped through a long­stand­ing part­ner­ship between the U.S. Army and the Cen­ters for Dis­ease Con­trol and Pre­ven­tion. It was repur­posed for Covid-19 after mul­ti­mil­lion-dol­lar tri­als spon­sored by the N.I.H. sug­gest­ed it could work against coro­n­avirus­es.

Despite Veklury’s ques­tion­able effec­tive­ness, the F.D.A. has also award­ed Gilead a “pri­or­i­ty review vouch­er” worth $75 to $100 mil­lion. This vouch­er can be used by Gilead or sold to a dif­fer­ent man­u­fac­tur­er to has­ten review of anoth­er drug appli­ca­tion. This would per­pet­u­ate the entry of oth­er treat­ments that are hur­ried­ly reviewed and, like remde­sivir, may be of uncer­tain ben­e­fit.

The dan­gers posed by the F.D.A.’s rush in approv­ing Vek­lury are com­pound­ed by the chaos of pre­sumed polit­i­cal inter­fer­ence by the Trump admin­is­tra­tion. But the weak­en­ing of F.D.A. stan­dards will most like­ly con­tin­ue under the Biden admin­is­tra­tion. When he was vice pres­i­dent, Joe Biden strong­ly endorsed the 21st-Cen­tu­ry Cures Act, and some in Con­gress are already push­ing for its next iter­a­tion, Cures 2.0.

If passed, it would fur­ther erode the F.D.A.’s evi­den­tiary stan­dards. Among Cures 2.0 pro­pos­als is mov­ing the basis for approval away from ran­dom­ized, con­trolled tri­als, long con­sid­ered the gold stan­dard of evi­dence, and instead rely­ing more on obser­va­tion­al evi­dence and sur­ro­gate mea­sures.

It is hard to ask peo­ple to wait for the evi­dence when there’s a treat­ment that could hold some promise, espe­cial­ly dur­ing a dev­as­tat­ing pan­dem­ic. But the hasty approval of expen­sive new treat­ments like remde­sivir isn’t the solu­tion. Doc­tors like us must feel con­fi­dent that the drugs approved by the F.D.A. are worth pre­scrib­ing to our patients.

Ravi Gup­ta (@rgupta729) is an inter­nal med­i­cine physi­cian and a fel­low at the Nation­al Clin­i­cian Schol­ars Pro­gram at the Uni­ver­si­ty of Penn­syl­va­nia. Resh­ma Ramachan­dran (@reshmagar) is a fam­i­ly med­i­cine physi­cian and a fel­low at the Nation­al Clin­i­cian Schol­ars Pro­gram at Yale Uni­ver­si­ty. They are both mem­bers of the Doc­tors for Amer­i­ca Drug Afford­abil­i­ty Action Team.

 

2a. Piv­ot­ing to dis­cus­sion and review of the polit­i­cal, finan­cial and cor­po­rate con­nec­tions to the devel­op­ment of med­i­c­i­nal treat­ments for, and vac­cines to pre­vent, Covid-19, we recap details rel­e­vant to the extra­or­di­nary tim­ing of a 4/29 announce­ment of favor­able results for a tri­al of remde­sivir. That announce­ment drove equi­ties mar­kets high­er and was ben­e­fi­cial to the stock of Gilead Sci­ences.

We present a Stat News arti­cle on the inter­nal delib­er­a­tions behind the deci­sions to mod­i­fy the NIAID study. Of par­tic­u­lar sig­nif­i­cance is the DSMB delib­er­a­tion. Note the time­line of the DSMB delib­er­a­tion, com­bined with the announce­ment on 4/29 that drove the mar­kets high­er.

  1. The deci­sion was made to cut it short before the ques­tion of remdesivir’s impact on mor­tal­i­ty could be answered: ” . . . .The Nation­al Insti­tute of Aller­gy and Infec­tious Dis­eases has described to STAT in new detail how it made its fate­ful deci­sion: to start giv­ing remde­sivir to patients who had been assigned to receive a place­bo in the study, essen­tial­ly lim­it­ing researchers’ abil­i­ty to col­lect more data about whether the drug saves lives — some­thing the study, called ACTT‑1, sug­gests but does not prove. In the tri­al, 8% of the par­tic­i­pants giv­en remde­sivir died, com­pared with 11.6% of the place­bo group, a dif­fer­ence that was not sta­tis­ti­cal­ly sig­nif­i­cant. A top NIAID offi­cial said he had no regrets about the deci­sion. ‘There cer­tain­ly was una­nim­i­ty with­in the insti­tute that this was the right thing to do,’ said H. Clif­ford Lane, NIAID’s clin­i­cal direc­tor. . . .”
  2. In addi­tion, patients sched­uled to receive place­bo received remde­sivir, instead. ” . . . . Steven Nis­sen, a vet­er­an tri­al­ist and car­di­ol­o­gist at the Cleve­land Clin­ic, dis­agreed that giv­ing place­bo patients remde­sivir was the right call. ‘I believe it is in society’s best inter­est to deter­mine whether remde­sivir can reduce mor­tal­i­ty, and with the release of this infor­ma­tion doing a place­bo-con­trolled tri­al to deter­mine if there is a mor­tal­i­ty ben­e­fit will be very dif­fi­cult,’ he said. ‘The ques­tion is: Was there a route, or is there a route, to deter­mine if the drug can pre­vent death?’ The deci­sion is ‘a lost oppor­tu­ni­ty,’ he said. . . .”
  3. Steven Nis­sen was not alone in his crit­i­cism of the NIAID’s deci­sion. ” . . . .Peter Bach, the direc­tor of the Cen­ter for Health Pol­i­cy and Out­comes at Memo­r­i­al Sloan Ket­ter­ing Can­cer Cen­ter, agreed with Nis­sen. ‘The core under­stand­ing of clin­i­cal research par­tic­i­pa­tion and clin­i­cal research con­duct is we run the tri­al rig­or­ous­ly to pro­vide the most accu­rate infor­ma­tion about the right treat­ment,’ he said. And that answer, he argued, should ide­al­ly have deter­mined whether remde­sivir saves lives. The rea­son we have shut our whole soci­ety down, Bach said, is not to pre­vent Covid-19 patients from spend­ing a few more days in the hos­pi­tal. It is to pre­vent patients from dying. ‘Mor­tal­i­ty is the right end­point,’ he said. . . .”
  4. Not only was the admin­is­tra­tion of remde­sivir instead of place­bo pri­or­i­tized, but the NIAID study itself was atten­u­at­ed! ” . . . . But the change in the study’s main goal also changed the way the study would be ana­lyzed. Now, the NIAID decid­ed, the analy­sis would be cal­cu­lat­ed when 400 patients out of the 1,063 patients the study enrolled had recov­ered. If remde­sivir turned out to be much more effec­tive than expect­ed, ‘inter­im’ analy­ses would be con­duct­ed at a third and two-thirds that num­ber.The job of review­ing these analy­ses would fall to a com­mit­tee of out­side experts on what is known as an inde­pen­dent data and safe­ty mon­i­tor­ing board, or DSMB. . . .”
  5. The per­for­mance of the DSMB for the remde­sivir study is note­wor­thy: ” . . . . But the DSMB for the remde­sivir study did not ever meet for an inter­im effi­ca­cy analy­sis, Lane said. All patients had been enrolled by April 20. The data for a DSMB meet­ing was cut off on April 22. The DSMB met and, on April 27, it made a rec­om­men­da­tion to the NIAID. . . .”
  6. The DSMB meet­ing on 4/27 deter­mined the switch from place­bo to remde­sivir. Of para­mount impor­tance is the fact that this was JUST BEFORE the 4/29 announce­ment that drove the mar­kets high­er and the same day on which key Trump aide–and for­mer Gilead Sci­ences lob­by­ist Joe Gro­gan resigned! ” . . . . . That deci­sion, Lane said, led the NIAID to con­clude that patients who had been giv­en place­bo should be offered remde­sivir, some­thing that start­ed hap­pen­ing after April 28. . . .”
  7. Dr. Ethan Weiss gave an accu­rate eval­u­a­tion of the NIAID study: ” . . . . ‘We’ve squan­dered an incred­i­ble oppor­tu­ni­ty to do good sci­ence,’ [Dr. Ethan] Weiss said. ‘If we could ever go back and do some­thing all over, it would be the infra­struc­ture to actu­al­ly learn some­thing. Because we’re not learn­ing enough.’ . . . .”

The remark­able han­dling of the NIAID study, the tim­ing of the announce­ment of the alto­geth­er lim­it­ed suc­cess of the atten­u­at­ed tri­al and the rise in equi­ties as a result of the announce­ment may be best under­stood in the con­text of the role played in Trump pan­dem­ic deci­sion-mak­ing by an elite group of bil­lion­aires and scientists–including con­vict­ed felon Michael Milken (the “junk bond king”).

  1. ” . . . . Call­ing them­selves ‘Sci­en­tists to Stop COVID-19,’ the col­lec­tion of top researchers, bil­lion­aires and indus­try cap­tains will act as an ‘ad hoc review board’ for the tor­rent of coro­n­avirus research, ‘weed­ing out’ flawed data before it reach­es pol­i­cy­mak­ersthe Wall Street Jour­nal report­ed on Mon­day. They are also act­ing as a go-between for phar­ma­ceu­ti­cal com­pa­nies seek­ing to build a com­mu­ni­ca­tion chan­nel with Trump admin­is­tra­tion offi­cials. The group . . . . has advised Nick Ayers, an aide to Vice Pres­i­dent Mike Pence, as well as oth­er agency heads, in the past month. Pence is head­ing up the White House coro­n­avirus task force. . . .”
  2. ” . . . The brainy bunch is led by Thomas Cahill, a 33-year-old doc­tor who became a ven­ture cap­i­tal­ist . . . . Cahill’s clout comes from build­ing con­nec­tions through his invest­ment firm, New­path Part­ners, with Sil­i­con Valley’s Peter Thiel, the founder of Pay­Pal, and bil­lion­aire busi­ness­men Jim Palot­ta and Michael Milken. . . .”

Note that Peter Thiel played a dom­i­nant role in bankrolling New­path Part­ners, and the oth­er finan­cial angel who ele­vat­ed Cahill–Brian Sheth–intro­duced him to Tom­my Hicks, Jr., the co-chair­man of the RNC. In FTR #‘s 1111 and 1112, we looked at Hicks’ net­work­ing with Steve Ban­non asso­ciate J. Kyle Bass, as well as his role in the inter-agency net­works dri­ving the anti-Chi­na effort.

” . . . . At the helm of the effort: The 33-year-old and very-much-under-the-radar ven­ture cap­i­tal­ist Tom Cahill, who leads life sci­ences-focused New­path Part­ners. Cahill com­plet­ed his M.D. and PhD at Duke Uni­ver­si­ty a mere two years ago before land­ing at blue-chip invest­ment firm Rap­tor Group through a friend. He went on to found New­path with some $125 mil­lion after impress­ing well-con­nect­ed names like ven­ture cap­i­tal­ist Peter Thiel and Vista Equi­ty Part­ners co-founder Bri­an Sheth. . . . It was through Sheth, for exam­ple, that Sci­en­tists to Stop Covid-19 con­nect­ed with the co-chair­man of the Repub­li­can Nation­al Com­mit­tee, Thomas Hicks Jr. . . .”

The fed­er­al gov­ern­men­t’s extreme focus on remde­sivir has been shaped, in large mea­sure, by the influ­ence of “Sci­en­tists to Stop COVID-19”:

  1. “Sci­en­tists to Stop Covid-19” is shep­herd­ing remde­sivir: ” . . . . Sci­en­tists to Stop COVID-19 rec­om­mends that in this phase, the U.S. Food and Drug Admin­is­tra­tion (FDA) should work to coor­di­nate with Gilead phar­ma­ceu­ti­cals to focus on expe­dit­ing the results of clin­i­cal tri­als of remde­sivir, a drug iden­ti­fied as a poten­tial treat­ment for COVID-19. The group also rec­om­mends admin­is­ter­ing dos­es of the drug to patients in an ear­ly stage of infec­tion, and notes remde­sivir will essen­tial­ly be a place­hold­er until a more effec­tive treat­ment is pro­duced.
  2. The group is doing so by atten­u­at­ing the reg­u­la­to­ry process for coro­n­avirus drugs: “Gov­ern­ment enti­ties and agen­cies appear to adhere to the rec­om­men­da­tions out­lined by the group, with the Jour­nal report­ing that the FDA and the Depart­ment of Vet­er­ans Affairs (VA) have imple­ment­ed some of the sug­ges­tions, name­ly relax­ing drug man­u­fac­tur­er reg­u­la­tions and require­ments for poten­tial coro­n­avirus treat­ment drugs. . . .”

We con­clude dis­cus­sion of the remde­sivir machi­na­tions with a piece about the tim­ing of the announce­ment of Grogan’s depar­ture.

” . . . . Gro­gan has served as the direc­tor of the White House Domes­tic Pol­i­cy Coun­cil since Feb­ru­ary 2019, over­see­ing a broad array of pol­i­cy issues includ­ing health care and reg­u­la­tion. . . . Gro­gan was one of the orig­i­nal mem­bers of the White House coro­n­avirus task force launched in late Jan­u­ary. . . . Gro­gan worked as a lob­by­ist for drug com­pa­ny Gilead Sci­ences before join­ing the Trump admin­is­tra­tion. . . .”

The depar­ture was announced in the Wall Street Jour­nal on the morn­ing of Wednes­day, April 29, the same day we got our first pub­lic reports of the NIAID clin­i­cal tri­al of remde­sivir that was pos­i­tive enough to show it short­ened the time to recov­ery and the same day the FDA grant­ed remde­sivir emer­gency use sta­tus. 

Note, again, the tim­ing of the DSM­B’s actions, as well as the influ­ence of “Sci­en­tists to Stop Covid-19.”

2b. Of par­tic­u­lar inter­est in the con­text of the pro­fes­sion­al mas­sag­ing of remde­sivir are the cir­cum­stances sur­round­ing the CDC’s clo­sure of the U.S. Army Med­ical Research Insti­tute of Infec­tious Dis­eases. The USAMRIID–located at Ft. Detrick–had host­ed Gilead Sci­ences’ ani­mal tri­als of remde­sivir. Remde­sivir was devel­oped to com­bat Ebo­la, and was a fail­ure in its ini­tial pro­fes­sion­al iter­a­tion.

In March of 2019, rhe­sus macaques were infect­ed with Ebo­la at the USAMRIID as part of a project to allow remde­sivir to be mar­ket­ed as an Ebo­la treat­ment with­out meet­ing the pro­fes­sion­al stan­dards of human test­ing. ” . . . This agree­ment was made pos­si­ble through a 2018 Nat­ur­al His­to­ry Study (NHS) of Ebo­la virus con­duct­ed by USAMRIID in close col­lab­o­ra­tion with Gilead Sci­ences, Inc., the spon­sor of remde­sivir devel­op­ment . . .”

Many of the safe­ty vio­la­tions cit­ed by the CDC in its cri­tique of USAMRIID safe­ty and secu­ri­ty pro­ce­dures con­cerned “non-human pri­mates” infect­ed with one or more “select agents” that were not named. The term “select agent” refers to a pathogen being used in lab­o­ra­to­ry pro­ce­dures. Whether the “select agent” was Ebo­la, and whether the safe­ty laps­es were in con­nec­tion with the remdesivir/rhesus mon­key tri­als was not dis­closed.

” . . . . Sev­er­al of the lab­o­ra­to­ry vio­la­tions the CDC not­ed in 2019 con­cerned ‘non-human pri­mates’ infect­ed with a ‘select agent’, the iden­ti­ty of which is unknown — it was redact­ed in all received doc­u­ments, because dis­clos­ing the iden­ti­ty and loca­tion of the agent would endan­ger pub­lic health or safe­ty, the agency says. In addi­tion to Ebo­la, the lab works with oth­er dead­ly agents like anthrax and small­pox. . . ..”

If, for the sake of argu­ment, SARS-CoV­‑2 research was indeed tak­ing plac­ing there was a very real risk of it escap­ing.

3a. Jonathan King, who has chaired the micro­bial phys­i­ol­o­gy study sec­tion for the NIH has sound­ed the alarm about “vac­cine research” mask­ing offen­sive bio­log­i­cal war­fare research:

Gene Wars: Mil­i­tary Con­trol Over the New Tech­nolo­gies by Charles Piller and Kei­th R. Yamamo­to; Beech Tree Books/William Mor­row [HC]; Copy­right 1988 by Charles Piller and Kei­th Yamamo­to; ISBN 0–688-07050–7; p. 217

. . . . King, who has chaired the micro­bial phys­i­ol­o­gy study sec­tion for the NIH, believes that with­out inten­sive inde­pen­dent scruti­ny, the Pen­ta­gon is free to obscure its true goals.

“The Defense Depart­ment appears to be pur­su­ing many nar­row, applied goals that are by nature offen­sive, such as the genet­ic ‘improve­ment’ of BW agents,” King says. “But to achieve polit­i­cal accept­abil­i­ty, they mask these inten­tions under forms of research, such as vac­cine devel­op­ment, which sound defen­sive. . . .

3b. Deeply dis­turb­ing, as well, is the news that the “pos­i­tive news” about vac­cine suc­cess and devel­op­ment has been gen­er­at­ed by press releas­es from the com­pa­nies that man­u­fac­ture them: 

Anoth­er Vac­cine Appears to Work Against the Virus” by Denise Grady; The New York Times; 11/17/2020.

. . . . But the com­pa­nies announced the find­ings in news releas­es, not in peer-reviewed sci­en­tif­ic jour­nals, and did not dis­close the detailed data that would allow out­side experts to eval­u­ate their claims. There­fore, the results can­not be con­sid­ered con­clu­sive. The fig­ures on effec­tive­ness may change as the stud­ies con­tin­ue. . . .

4a. Mod­er­na’s vac­cine devel­op­ment was over­seen by an unnamed Pen­ta­gon offi­cial:

“Pol­i­tics, Sci­ence and the Remark­able Race for a Viable Vac­cine” by Sharon LaFraniere, Katie Thomas, Noah Wei­land, David Gelles, Sheryl Gay Stol­berg and Denise Grady; The New York Times; 11/22/2020.

. . . . Moderna’s team was head­ed by a Defense Depart­ment offi­cial whom com­pa­ny exec­u­tives described only as “the major,” say­ing they don’t know if his name is sup­posed to be a secret. . . . .

4b. The rapid spread of the dis­ease is ben­e­fit­ting the speed-up of vac­cine research.

One Ben­e­fit of Surge in Cas­es: A Faster Eval­u­a­tion of Vac­cines” by Rebec­ca Rob­bins; The New York Times; 11/19/2020.

The coro­n­avirus is spread­ing out of con­trol in the Unit­ed States, over­whelm­ing health sys­tems and killing more than 1,100 Amer­i­cans a day. But there is a slen­der sil­ver lin­ing: It is has­ten­ing the test­ing of vac­cines that could even­tu­al­ly end the pan­dem­ic.

The surg­ing virus has already allowed Pfiz­er and Mod­er­na to accel­er­ate the test­ing of their vac­cines, which appear to be very effec­tive at pre­vent­ing Covid-19.

And if, as seems inevitable, the virus con­tin­ues to pro­lif­er­ate — it is spread­ing faster than ever in the Unit­ed States and some oth­er coun­tries — it is like­ly to speed the eval­u­a­tions of promis­ing vac­cine can­di­dates from oth­er phar­ma­ceu­ti­cal com­pa­nies. . . .

5. Of great sig­nif­i­cance is the cen­tral role of the mil­i­tary in the devel­op­ment of treat­ment for Covid-19:

“Military’s Role in Vac­cine Will Be Behind the Scenes, Despite Trump’s Claims” by Jen­nifer Stein­hauer; The New York Times; 11/27/2020.

When Pres­i­dent Trump talks about efforts to deliv­er the coro­n­avirus vac­cine to mil­lions of Amer­i­cans eager to return to their nor­mal lives, he often says he is “count­ing on the mil­i­tary” to get it done. . . .

. . . . In real­i­ty, the role of the mil­i­tary has been less pub­lic and more per­va­sive than this char­ac­ter­i­za­tion sug­gests. . . .

. . . . Scores of Defense Depart­ment employ­ees are laced through the gov­ern­ment offices involved in the effort, mak­ing up a large por­tion of the fed­er­al per­son­nel devot­ed to the effort. Those num­bers have led some cur­rent and for­mer offi­cials at the Cen­ters for Dis­ease Con­trol and Pre­ven­tion to pri­vate­ly grum­ble that the military’s role in Oper­a­tion Warp Speed was too large for a task that is, at its core, a pub­lic health cam­paign.

“Frankly, it has been breath­tak­ing to watch,” said Paul Ostrows­ki, the direc­tor of sup­ply, pro­duc­tion and dis­tri­b­u­tion for Oper­a­tion Warp Speed. He is a retired Army lieu­tenant gen­er­al who was select­ed to man­age logis­tics for the pro­gram by Gen. Gus­tave F. Per­na, the chief oper­at­ing offi­cer for Oper­a­tion Warp Speed.

Wran­gling vol­un­teers for four expe­dit­ed vac­cine tri­als — a chore in any cir­cum­stance — became even more chal­leng­ing dur­ing a pan­dem­ic, when ask­ing hun­dreds of thou­sands of sub­jects to sit in hos­pi­tal wait­ing rooms and oth­er health care cen­ters was often not fea­si­ble. The Pen­ta­gon has helped three com­pa­nies — AstraZeneca, Mod­er­na and Janssen — set up pop-up sites to con­duct tri­als at 63 loca­tions nation­wide. . . .

. . . . These are the types of things that the mil­i­tary can quick­ly obtain through its con­tract­ing sys­tem, as well as any per­mits need­ed to set it all up. “We have the abil­i­ty to set up large-scale hous­ing capa­bil­i­ties through­out the entire world at a moment’s notice,” Gen­er­al Ostrows­ki said. . . .

. . . . Mil­i­tary offi­cials also came up with the clever idea — if it works — to coor­di­nate the deliv­ery of vac­cines to drug­stores, med­ical cen­ters and oth­er immu­niza­tion sites by send­ing kits full of nee­dles, syringes and alco­hol wipes. Vac­cine mak­ers will be alert­ed when the kits arrive at an immu­niza­tion site so they know to ship dos­es. Once the first dose is giv­en, the man­u­fac­tur­er will be noti­fied so it can send the sec­ond dose with a patient’s name attached sev­er­al weeks lat­er. . . .

. . . . The mil­i­tary will also mon­i­tor vac­cine dis­tri­b­u­tion through an oper­a­tions cen­ter. “They will know where every vac­cine dose is,” Mr. [Paul] Man­go said on a call with reporters. [Man­go is the deputy chief of staff for pol­i­cy at the Depart­ment of Health and Human Ser­vices and the main spokesman for Oper­a­tion Warp Speed.–D.E.] “If a vac­cine dose is at risk of expir­ing, they will gide the move­ment of that to some­place else.” . . . . 

6. Piv­ot­ing to dis­cus­sion of the pol­i­tics of Lyme Dis­ease treat­ment, we note that legal and reg­u­la­to­ry rul­ings have enabled the patent­ing of liv­ing organ­isms and that has exac­er­bat­ed the mon­e­tiz­ing of Lyme Dis­ease treat­ment. That mon­e­ti­za­tion, in turn, has adverse­ly affect­ed the qual­i­ty of care for afflict­ed patients. ” . . . . All of a sud­den, the insti­tu­tions that were sup­posed to be pro­tec­tors of pub­lic health became busi­ness part­ners with Big Phar­ma. The uni­ver­si­ty researchers who had pre­vi­ous­ly shared infor­ma­tion on dan­ger­ous emerg­ing dis­eases were now delay­ing pub­lish­ing their find­ings so they could become entre­pre­neurs and prof­it from patents through their uni­ver­si­ty tech­nol­o­gy trans­fer groups. We essen­tial­ly lost our sys­tem of sci­en­tif­ic checks and bal­ances. And this, in turn, has under­mined patient trust in the insti­tu­tions that are sup­posed to ‘do no harm.’ . . .”

Bit­ten: The Secret His­to­ry of Lyme Dis­ease and Bio­log­i­cal Weapons by Kris New­by; Harper­Collins [HC]; Copy­right 2019 by Kris New­by; ISBN 9780062896728; pp. 229–230.

. . . . Think­ing back on my research for the Lyme doc­u­men­tary Under Our Skin, I con­clud­ed that there was much more mon­ey at stake with Lyme Dis­ease. It was the first major new dis­ease dis­cov­ered after the Bayh-Dole Act and the Dia­mond v. Chakrabar­ty Supreme Court deci­sion made it pos­si­ble for the NIH, the CDC, and uni­ver­si­ties to patent and prof­it from “own­er­ship” of live organ­isms. When the causative organ­ism behind Lyme dis­ease was announced, some­thing akin to the Okla­homa Land Rush of 1889 began, as sci­en­tists with­in these insti­tu­tions began furi­ous­ly fil­ing patents on the sur­face pro­teins and DNA of the Lyme spiro­chete, hop­ing to prof­it from future vac­cines and diag­nos­tic tests that used these markers–for exam­ple, an NIH employ­ee who patents a bac­te­r­i­al sur­face pro­tein used in a com­mer­cial test kit or a vac­cine could receive up to $150,000 in roy­al­ty pay­ments a year, an amount that might dou­ble his or her annu­al salary. All of a sud­den, the insti­tu­tions that were sup­posed to be pro­tec­tors of pub­lic health became busi­ness part­ners with Big Phar­ma. The uni­ver­si­ty researchers who had pre­vi­ous­ly shared infor­ma­tion on dan­ger­ous emerg­ing dis­eases were now delay­ing pub­lish­ing their find­ings so they could become entre­pre­neurs and prof­it from patents through their uni­ver­si­ty tech­nol­o­gy trans­fer groups. We essen­tial­ly lost our sys­tem of sci­en­tif­ic checks and bal­ances. And this, in turn, has under­mined patient trust in the insti­tu­tions that are sup­posed to “do no harm.”

With Lyme dis­ease, there’s no prof­it incen­tive for proac­tive­ly treat­ing some­one with a few weeks of inex­pen­sive, off-patent antibi­otics. It’s the patentable vac­cines and manda­to­ry tests-before-treat­ment that bring in the steady rev­enues year after year. . . . 

7. Bit­ten author Kris New­by went up against the “Lyme Dis­ease estab­lish­ment” in an attempt to find out why the dis­ease was being mis-diag­nosed and inef­fec­tive­ly treat­ed. Strik­ing­ly, a FOIA suit she filed was stonewalled, before final­ly yield­ing the doc­u­ments she had so long sought.

The “experts” and their agen­da was neat­ly, and alarm­ing­ly, summed up by Ms. New­by:

” . . . . The emails revealed a dis­turb­ing pic­ture of a nonof­fi­cial group of gov­ern­ment employ­ees and guide­lines authors that had been set­ting the nation­al Lyme dis­ease research agen­da with­out pub­lic over­sight or trans­paren­cy. . . . Bot­tom line, the guide­lines authors reg­u­lar­ly con­vened in gov­ern­ment-fund­ed, closed-door meet­ings with hid­den agen­das that lined the pock­ets of aca­d­e­m­ic researchers with sig­nif­i­cant com­mer­cial inter­ests in Lyme dis­ease tests and vac­cines. A large per­cent­age of gov­ern­ment grants were award­ed to the guide­line authors and/or researchers in their labs. Part of the group’s stat­ed mis­sion, culled from these FOIA emails, was to run a covert ‘dis­in­for­ma­tion war’ and a ‘sociopo­lit­i­cal offen­sive’ to dis­cred­it Lyme patients, physi­cians, and jour­nal­ists who ques­tioned the group’s research and motives. In the FOIA-obtained emails, Lyme patients and their treat­ing physi­cians were called ‘loonies’ and ‘quacks’ by Lyme guide­lines authors and NIH employ­ees. . . .”

Bit­ten: The Secret His­to­ry of Lyme Dis­ease and Bio­log­i­cal Weapons by Kris New­by; Harper­Collins [HC]; Copy­right 2019 by Kris New­by; ISBN 9780062896728; pp. 121–124.

. . . . In the IDSA [Infec­tious Dis­eases Soci­ety of Amer­i­ca] guide­lines, chron­ic Lyme isn’t clas­si­fied as an ongo­ing, per­sis­tent infec­tion; it’s con­sid­ered either an autoim­mune syn­drome (in which a body’s immune sys­tem attacks itself) or a psy­cho­log­i­cal con­di­tion caused by “the aches and pains of dai­ly liv­ing” or “pri­or trau­mat­ic psy­cho­log­i­cal events.” These guide­lines were often used by med­ical insur­ers to deny treat­ment, and many of its authors are paid con­sult­ing fees to tes­ti­fy as expert wit­ness­es in these insur­ance cas­es. In some states, the guide­line rec­om­men­da­tions take on the force of law, so that Lyme physi­cians who prac­tice out­side them are at risk of los­ing their med­ical licens­es.

The pro­tes­tors were angry because, as part of a 2008 antitrust set­tle­ment brought by Con­necti­cut attor­ney gen­er­al Richard Blu­men­thal (now a sen­a­tor), the IDSA guide­lines were sup­posed to appoint an expert pan­el with­out bias­es or con­flicts to do a re-review of the guide­lines. In the set­tle­ment press release, Blu­men­thal had writ­ten, “My office uncov­ered undis­closed finan­cial inter­ests held by sev­er­al of the most pow­er­ful IDSA pan­elists. The IDSA’s guide­line pan­el improp­er­ly ignored or min­i­mized con­sid­er­a­tion of alter­na­tive med­ical opin­ion and evi­dence regard­ing chron­ic Lyme dis­ease, poten­tial­ly rais­ing seri­ous ques­tions about whether the rec­om­men­da­tions reflect­ed all rel­e­vant sci­ence.”

In response, the IDSA lead­er­ship select­ed a review pan­el of doc­tors and sci­en­tists, and they deter­mined that “No changes or revi­sions to the 2006 Lyme guide­lines are nec­es­sary at this time.”

Lor­raine John­son, JD, MBA, the chief exec­u­tive offi­cer of LymeDisease.org, and a cham­pi­on of the IDSA antitrust suit, main­tains that the review pan­el was stacked with like-mind­ed cronies of the orig­i­nal guide­lines’ authors and was there­fore biased. She cites the recent arti­cle by research qual­i­ty expert and Stan­ford pro­fes­sor John Ioan­ni­dis, MD, DSc, who rec­om­mends that “Pro­fes­sion­al soci­eties should con­sid­er dis­en­tan­gling their spe­cial­ists from guide­lines and dis­ease def­i­n­i­tions and lis­ten to what more impar­tial stake­hold­ers think about their prac­tices.”

Today, in 2019, these con­tro­ver­sial guide­lines and dis­put­ed tests are still influ­enc­ing Lyme patient care.

Peo­ple often ask me why the IDSA and CDC would sup­port the prob­lem­at­ic two-tier Lyme test. Dur­ing my doc­u­men­tary research, I tried to get an answer to this ques­tion with a Free­dom of Infor­ma­tion Act (FOIA) request that solicit­ed emails between three CDC employ­ees and the IDSA guide­lines authors. For five years the CDC strung me along with friv­o­lous denials, unex­plained delays, and false promis­es. In essence, the delays became an ille­gal, off-the-books FOIA denial. Some delays were attrib­uted to under­staffing, year-end dead­lines, and CDC per­son­nel out for vaca­tion. At one point, my unan­swered calls were blamed on a phone “dead zone” in the CDC’s new FOIA office. After the Lyme doc­u­men­tary Under Our Skin was released, I decid­ed to dou­ble-down on my efforts to dis­lodge the FOIA request. My con­gressper­son sent sev­er­al let­ters to the CDC. The direc­tor of the doc­u­men­tary wrote a let­ter to Pres­i­dent Oba­ma. The FOIA ombuds­man in the Office of Gov­ern­ment Infor­ma­tion Ser­vices repeat­ed­ly pres­sured the CDC to ful­fill my request. I pub­lished blog posts about my plight and enlist­ed the sup­port of a num­ber of orga­ni­za­tions ded­i­cat­ed to ensur­ing gov­ern­ment trans­paren­cy. Final­ly, the CDC sent three-thou­sand-plus FOIA pages, and I then under­stood its moti­va­tion for hav­ing delayed their release.

The emails revealed a dis­turb­ing pic­ture of a nonof­fi­cial group of gov­ern­ment employ­ees and guide­lines authors that had been set­ting the nation­al Lyme dis­ease research agen­da with­out pub­lic over­sight or trans­paren­cy. Inves­tiga­tive jour­nal­ist Mary Beth Pfeif­fer of the Pough­keep­sie Jour­nal was giv­en access to these emails, and on May 20, 2013. She pub­lished an expose on this group’s abuse of pow­er.

Bot­tom line, the guide­lines authors reg­u­lar­ly con­vened in gov­ern­ment-fund­ed, closed-door meet­ings with hid­den agen­das that lined the pock­ets of aca­d­e­m­ic researchers with sig­nif­i­cant com­mer­cial inter­ests in Lyme dis­ease tests and vac­cines. A large per­cent­age of gov­ern­ment grants were award­ed to the guide­line authors and/or researchers in their labs.

Part of the group’s stat­ed mis­sion, culled from these FOIA emails, was to run a covert “dis­in­for­ma­tion war” and a “sociopo­lit­i­cal offen­sive” to dis­cred­it Lyme patients, physi­cians, and jour­nal­ists who ques­tioned the group’s research and motives. In the FOIA-obtained emails, Lyme patients and their treat­ing physi­cians were called “loonies” and “quacks’ by Lyme guide­lines authors and NIH employ­ees.

Because my FOIA request end­ed up tak­ing five years to process, Under Our Skin had been made and released with­out answer­ing an impor­tant ques­tion: Were the gov­ern­ment offi­cials respon­si­ble for man­ag­ing Lyme dis­ease health pol­i­cy being inap­pro­pri­ate­ly influ­enced by out­side com­mer­cial inter­ests?

Through my FOIA request, I found that a major­i­ty of the authors of the 2006 IDSA Lyme diag­no­sis and treat­ment guide­lines held direct or indi­rect com­mer­cial inter­ests relat­ed to Lyme dis­ease. By defin­ing the dis­ease and endors­ing tests or vac­cines for which they were patent hold­ers, they and their insti­tu­tions made more mon­ey.

Yet, now Willy’s con­fes­sion had added anoth­er poten­tial dimen­sion to the sto­ry, anoth­er rea­son for the CDC to be under­count­ing Lyme cases—maybe gov­ern­ment offi­cials knew that some­thing else, a pathogen in addi­tion to Bor­re­lia, pos­si­bly a bio-weapon, was caus­ing the prob­lems, and they want­ed to keep a lid on it. . . .

Discussion

One comment for “FTR #1166 Bio-Psy-Op Apocalypse Now, Part 22: A Pound of Cure, Part 1”

  1. Remem­ber Oya­Gen? That was the small Rochester, New York, based biotech com­pa­ny dis­cussed in FTR#1121 that claimed back in March 2020 to have dis­cov­ered a com­pound that sound­ed almost mirac­u­lous in the con­text of the emerg­ing coro­n­avirus pan­dem­ic. That com­pound, dubbed Oya1, was described as effec­tive­ly ster­il­iz­ing cell cul­tures of the SARS-CoV­‑2 virus. Best of all, it did­n’t require a new round of safe­ty test­ing because it had been exam­ined as a can­cer drug back in the 1960s and safe dosages were already known. And yet, despite this won­der­ful news, the founder of Oya­Gen, Harold Smith, was essen­tial­ly plead­ing with the media to bring atten­tion to the fact that the com­pa­ny was­n’t get­ting the kind of expe­dit­ed per­mis­sion by US author­i­ties to car­ry out COVID-relat­ed tests that Smith felt the sit­u­a­tion war­rant­ed. Adding to the mys­tery is the fact that Oya­Gen had been work­ing direct­ly with the US gov­ern­men­t’s fed­er­al inte­grat­ed research facil­i­ty in Fort Det­rick, Mary­land, when car­ry­ing out this research. So the US bio­med­ical mil­i­tary research com­plex was involved with the gov­ern­ment appeared to be drag­ging its feet on.

    In the end, we nev­er real­ly learned what became of Oya1 or that promis­ing research. Was that the last we were to hear about Oya1 and its incred­i­ble effi­ca­cy against COVID? Or were we going to even­tu­al­ly hear an update? Well, we final­ly got an update and wow is it kind of a doozy. It’s real­ly a pair of updates.

    First, there was update on Wednes­day about Oya1 and COVID. As before, it’s local Rochester, New York, news cov­er­ing this, despite the fact that this should arguably be inter­na­tion­al news: Oya­Gen announced the dis­cov­ery that com­bin­ing Oya1 with remde­sivir results in sub­stan­tial­ly bet­ter results than just remde­sivir We aren’t giv­en any addi­tion­al infor­ma­tion on the nature of the stud­ies that demon­strate the val­ue of the Oya1 + remde­sivir com­bi­na­tion, although it does­n’t sound like it was clin­i­cal tri­als on infect­ed patients because Harold Smith reit­er­at­ed his com­plaint that the FDA wants more test­ing at the cost of mil­lions of dol­lars before clin­i­cal tri­als can begin for the COVID use.

    So it sounds like, once again, we are learn­ing that Oya1 is a major improve­ment over remde­sivir alone and yet, once again, clin­i­cal tri­als aren’t actu­al­ly under­way because the FDA refus­es to fast-track them. 10 months after we first heard from Oya­Gen about their dis­cov­ery that Oya1 was effec­tive­ly ster­il­iz­ing cell cul­tures of the SARS-CoV­‑2 virus, fol­lowed by Harold Smith’s pub­lic cries for gov­ern­ment approval to accel­er­ate clin­i­cal tri­als, we’re now learn­ing that Oya1 appears to actu­al­ly make remde­sivir use­ful against COVID. Isn’t this at least some­what scan­dalous?

    And then there’s the sec­ond recent update we got from Oya­Gen. This update was pub­lished direct­ly by Oya­Gen itself over the PRNewswire ser­vice last week, announc­ing a new study joint­ly on Oya1 con­duct­ed by Oya­Gen. Like the study last year that demon­strat­ed Oya1’s effi­ca­cy against SARS-CoV­‑2, this study was done in col­lab­o­ra­tion with the NIH/NIAID Inte­grat­ed Research Facil­i­ty at Fort Det­rick. But it was­n’t a study of Oya1’s effects on COVID. Instead, it was a study on Oya1’s effects on Ebo­la. Specif­i­cal­ly, it was a study that demon­strat­ed the util­i­ty of a new screen­ing plat­form for antivi­ral drugs that iden­ti­fies drugs that inter­fere with a par­tic­u­lar com­po­nent of the virus — the viral matrix (VP40) pro­tein — which should, in the­o­ry, dis­rupt the abil­i­ty of the virus to repli­cate itself.

    Not only did the study find that Oya1 is far more effec­tive than remde­sivir at treat­ing Ebo­la, it also found that com­bin­ing Oya1 and remde­sivir yield­ed the best over­all results and required less of each drug. It sure sounds a lot like the sto­ry of Oya1 vs remde­sivir against SARS-CoV­‑2. Keep in mind that remde­sivir was orig­i­nal­ly designed as a drug for Ebo­la. Also recall the 2019 study where remde­sivir was com­pared to three oth­er drugs as an Ebo­la treat­ment and con­sis­tent­ly came in as the least effec­tive.

    But there was anoth­er sig­nif­i­cant find­ing in Oya­Gen’s new study: Oya1 was unex­pect­ed­ly found to be high­ly effec­tive against a vari­ety of oth­er virus­es relat­ed to Ebo­la that they test­ed it against. The close­ly-relat­ed Mar­burg virus (MARV), along with the unre­lat­ed Las­sa virus (LASV), cow­pox virus (CPXV), and vac­cinia virus (VACV). And it’s not at all clear HOW the drug is hav­ing these unre­lat­ed virus­es because they don’t express VP40-like pro­teins. Based on these find­ings, the researchers con­clude that Oya1 (called “san­gi­vamycin” in the pub­li­ca­tion) could be a good can­di­date as a broad-spec­trum antivi­ral drug. This is a huge find­ing if true, in part because iden­ti­fy­ing broad-spec­trum anti-viral drugs has long been a major goal of pub­lic health offi­cials as a key tool for deal­ing with emerg­ing virus­es and remde­sivir has long been cham­pi­oned as a pos­si­ble broad-spec­trum drug, despite the dis­ap­point­ing results.

    All in all, these two announce­ments from Oya­Gen pro­vide fur­ther evi­dence that Oya1 might actu­al­ly have been the mir­a­cle drug the world was search­ing for 10 months ago when it became clear we were in store for a glob­al pan­dem­ic. And yet inter­est in the drug has remained tepid at best, despite the fact that this research is being pro­duced in part­ner­ship with the NIH and Fort Det­rick. It’s a real mys­tery.

    Ok, first, here’s an arti­cle from a local Rochester news out­let about Oya­Gen’s new announce­ment that the Oya1 + remde­sivir com­bi­na­tion is a lot more effec­tive than just remde­sivir alone, the kind of find­ing that should gen­er­ate glob­al head­lines but remains rel­e­gat­ed to local Rochester news:

    13WHAM

    ROC com­pa­ny reports break­throughs in drug to treat COVID; focus remains on vac­cine

    by Jane Flasch Wednes­day,
    Jan­u­ary 13th 2021

    Rochester, N.Y. — A drug that stops COVID-19 from spread­ing from cell to cell in the body: that dis­cov­ery near­ly a year ago has lead to more break­throughs, accord­ing to the com­pa­ny behind it.

    Yet one thing is stop­ping it from help­ing those who could use it most.

    “Peo­ple are wait­ing in line for a vac­cine. No one talk­ing about what you do to improve things if you are sick now,” said Dr. Harold Smith, founder and Chief Exec­u­tive Offi­cer of Oya­Gen.

    Over the last year, sci­en­tists have put aside research into can­cer and HIV — com­bin­ing efforts in the race to find a vac­cine to end the COVID pan­dem­ic. Now, that vac­cine is here — yet build­ing immu­ni­ty takes weeks and two dos­es.

    That is time that works against thou­sands in our com­mu­ni­ty who already have — or will — become infect­ed.

    “You don’t have time, if you’re sick already, in order to be vac­ci­nat­ed,” Dr. Smith says. “You need a med­ical coun­ter­mea­sure.”

    When the virus first sur­faced in Wuhan, Chi­na last year, a fed­er­al lab request­ed sam­ples of a com­pound called Oya 1 to mix with the live virus.

    Test sam­ples viewed under a micro­scope show a clear “before” and “after” that indi­cates prop­er­ties that allowed the virus to grow and spread were neu­tral­ized.

    In the months since these ear­ly tests, Oya­Gen has dis­cov­ered anoth­er break­through in con­junc­tion with a drug called Remde­sivir.

    Remedesivir alone is only mild­ly effec­tive in treat­ing the virus. That changed when mixed with Oya 1.

    “We were able to improve how well they work by com­bin­ing them and also to reduce the amount of drug that was nec­es­sary,” said Dr. Smith.

    Oya 1 was approved for can­cer treat­ment in the 1960s and declared safe for adults and chil­dren after clin­i­cal test­ing. It was lat­er shelved when more effec­tive treat­ments came along.

    The Food and Drug Admin­is­tra­tion often requires new clin­i­cal tri­als when a drug is repur­posed for a new use.

    Dr. Smith says the FDA wants more test­ing at the cost of mil­lions of dol­lars before clin­i­cal tri­als can begin for the COVID use.

    Yet he says fed­er­al efforts and crit­i­cal fund­ing have gone almost exclu­sive­ly to devel­op­ment of vac­cines.

    “It should have direct­ed a sig­nif­i­cant por­tion of our fed­er­al dol­lars into what we do as a stop-gap,” he said. “How do we treat peo­ple who are get­ting sick and are sick? A vac­cine is not the answer to that.”

    ...

    ———–

    “ROC com­pa­ny reports break­throughs in drug to treat COVID; focus remains on vac­cine” by Jane Flasch; 13WHAM; 01/13/2021

    “Remedesivir alone is only mild­ly effec­tive in treat­ing the virus. That changed when mixed with Oya 1.”

    So remde­sivir alone is only midld­ly effec­tive against COVID and yet Oya1 was shown last year to be high­ly effec­tive in cell cul­tures and the Oya1 + remde­sivir com­bi­na­tion is even more effec­tive. That makes it sound like Oya1 is doing most of the work but remde­sivir does actu­al­ly help Oya1 when used in com­bi­na­tion. This should be a huge find­ing trum­pet­ed around the world, and yet no one cares. Instead, we are against hear­ing Smith com­plain about the FDA refus­ing to fast-track clin­i­cal stud­ies at the same time major fed­er­al fund­ing has gone towards vac­cines. Although, to cor­rect Smith, there has been one major area of non-vac­cine ther­a­peu­tics that the US gov­ern­ment has spent sig­nif­i­cant mon­ey on and that’s remde­sivir. Again, why isn’t this more scan­dalous?

    ...
    The Food and Drug Admin­is­tra­tion often requires new clin­i­cal tri­als when a drug is repur­posed for a new use.

    Dr. Smith says the FDA wants more test­ing at the cost of mil­lions of dol­lars before clin­i­cal tri­als can begin for the COVID use.

    Yet he says fed­er­al efforts and crit­i­cal fund­ing have gone almost exclu­sive­ly to devel­op­ment of vac­cines.

    “It should have direct­ed a sig­nif­i­cant por­tion of our fed­er­al dol­lars into what we do as a stop-gap,” he said. “How do we treat peo­ple who are get­ting sick and are sick? A vac­cine is not the answer to that.”
    ...

    Ok, now here’s the next piece of news about Oya1 that should be very big news: a joint OyaGen/NIH study found Oya1 to be effec­tive against not just Ebo­la but a broad vari­ety of virus­es, sug­gest­ing Oya1 might be the much sought-after “broad-spec­trum” antivi­ral drug virol­o­gists have long desired. And yet this announce­ment was­n’t in a news piece. It was a PRNewsire piece released by Oya­Gen itself:

    PRNewswire

    Oya­gen, Inc. Pub­lish­es Study On Its OYA1 As A “High­ly Effec­tive” Exper­i­men­tal Drug Can­di­date For Treat­ing Infec­tions By The Ebo­la Virus

    News pro­vid­ed by
    Oya­Gen, Inc.

    Jan 07, 2021, 04:00 ET

    ROCHESTER, N.Y., Jan. 7, 2021 /PRNewswire/ — Oya­Gen, Inc. announced today pub­li­ca­tion in VIRUSES, a peer reviewed jour­nal, of stud­ies car­ried out by Oya­Gen in col­lab­o­ra­tion with NIH/NIAID Inte­grat­ed Research Facil­i­ty at Fort Det­rick MD. This Study iden­ti­fied OYA1 as a “high­ly effec­tive” antivi­ral against sev­er­al virus­es includ­ing Ebo­la and Las­sa virus­es.

    Ben­nett et al., A Nov­el Ebo­la Virus VP40 Matrix Pro­tein-Based Screen­ing for Iden­ti­fi­ca­tion of Nov­el Can­di­date Med­ical Coun­ter­mea­sures.’ (2021) Virus­es 13:52 https://doi.org/10.3390/v13010052

    About OYA1. OYA1 (a.k.a. san­gi­vamycin) has broad-spec­trum antivi­ral activ­i­ty in lab­o­ra­to­ry-based assays against sev­er­al virus­es. The pub­lished study results showed that OYA1 was “high­ly effec­tive” in reduc­ing the spread of Ebo­la Virus infec­tion in lab­o­ra­to­ry tests with the live Ebo­la virus car­ried out by NIAID. The data also sug­gest that OYA1 could be sig­nif­i­cant­ly more potent than Gilead Sci­ence’s remde­sivir. In vit­ro stud­ies showed that when OYA1 is dosed with remde­sivir both com­pounds are marked­ly more effec­tive inhibit­ing Ebo­la virus repli­ca­tion and do so at much low­er dos­es than is need­ed with either com­pound alone. OYA1 proved equal­ly effec­tive in stop­ping Ebo­la infec­tiv­i­ty when it was added at the time of infec­tion or 24 hours after an infec­tion.

    OYA1 was pre­vi­ous­ly test­ed by the Nation­al Can­cer Insti­tute for its poten­tial to treat a vari­ety of can­cers in the 1960’s. In those ear­li­er clin­i­cal tri­als, 88 men, women and chil­dren received a range of dos­es and a dose fre­quen­cy up to 120 days with no adverse side effects. OYA1 was aban­doned as a drug can­di­date for can­cer because it had no effect in reduc­ing tumor bur­den. Pre­clin­i­cal ani­mal safe­ty stud­ies also per­formed in the 1960’s and recent­ly repeat­ed by Oya­Gen iden­ti­fied safe dose ranges and showed the OYA1 was retained in the tis­sues of the body for sev­er­al days at con­cen­tra­tions approx­i­mate­ly half of the orig­i­nal dose. OYA1 has a sim­ple chem­i­cal syn­thet­ic path­way start­ing with read­i­ly avail­able com­pounds and is sta­ble as a dry pow­der for years.

    Dr. Harold Smith, founder and CEO of Oya­Gen said that: “The new­ly pub­lished find­ings are very encour­ag­ing and sug­gest that OYA1 may be a high­ly effec­tive treat­ment can­di­date for Ebo­la and Las­sa infec­tions. Oya­Gen’s lead drug can­di­date for Ebo­la may also improve the effi­ca­cy of remde­sivir in treat­ing Ebo­la infec­tions as com­bi­na­tion ther­a­py and there­by also may reduce the poten­tial emer­gence of drug resis­tant viral strains that are often seen when only one treat­ment modal­i­ty is used to com­bat infec­tious dis­eases.” “The pub­lished data are con­sis­tent with pri­or pub­lished stud­ies that show when OYA1 con­cen­tra­tions were high enough to sup­press cell growth in the lab, it slowed cell divi­sion (cyto­sta­t­ic) but did not kill the cells. These find­ings are con­sis­tent with human clin­i­cal tri­als that showed that the OYA1 is safe and well tol­er­at­ed in humans. We also not­ed that in com­par­ing the data report­ed in our pub­li­ca­tion to the clin­i­cal tri­al data from the 1960s that the amount of OYA1 antic­i­pat­ed to be required to inhib­it greater that 90% of virus repli­ca­tion appears to be at the low­er dos­es of drug than were giv­en to human sub­jects dur­ing the can­cer clin­i­cal tri­als.

    Oya­Gen Inc is a pri­vate­ly held Biotech­nol­o­gy Com­pa­ny locat­ed in Rochester NY. Oya­Gen is focused on the iden­ti­fi­ca­tion and pre­clin­i­cal devel­op­ment of nov­el ther­a­peu­tics for the treat­ment of viral dis­eases includ­ing HIV, Coro­n­avirus and Ebo­la.

    For more infor­ma­tion on Oya­Gen, Inc., please vis­it the com­pa­ny’s web­site at http://www.oyageninc.com and fol­low us on Face­book at http://www.facebook.com/OyaGeninc, or call Oya­Gen, Inc. at (585) 697‑4351. The stud­ies report­ed were sup­port­ed in part by Oya­Gen, Inc and in part through the Bat­telle Memo­r­i­al Insti­tute’s for­mer prime con­tract with the Nation­al Insti­tute of Aller­gy and Infec­tious Dis­eases (NIAID) under Con­tract No. HHSN272200700016I and Lauli­ma Gov­ern­ment Solu­tions, LLC’s cur­rent prime con­tract with NIAID under Con­tract No. HHSN272201800013C (S.Y., J.L.). C.L.F., E.N.P., Y.C., J.D., and J.H.K. per­formed this work as for­mer employ­ees of Bat­telle Memo­r­i­al Insti­tute and cur­rent employ­ees of Tun­nell Gov­ern­ment Ser­vices (TGS), a sub­con­trac­tor of Lauli­ma Gov­ern­ment Solu­tions, LLC under Con­tract No. HHSN272201800013C.

    SOURCE Oya­Gen, Inc.

    ————–

    “Oya­gen, Inc. Pub­lish­es Study On Its OYA1 As A “High­ly Effec­tive” Exper­i­men­tal Drug Can­di­date For Treat­ing Infec­tions By The Ebo­la Virus” pro­vid­ed by Oya­Gen, Inc.; PRNewswire; 01/07/2021

    About OYA1. OYA1 (a.k.a. san­gi­vamycin) has broad-spec­trum antivi­ral activ­i­ty in lab­o­ra­to­ry-based assays against sev­er­al virus­es. The pub­lished study results showed that OYA1 was “high­ly effec­tive” in reduc­ing the spread of Ebo­la Virus infec­tion in lab­o­ra­to­ry tests with the live Ebo­la virus car­ried out by NIAID. The data also sug­gest that OYA1 could be sig­nif­i­cant­ly more potent than Gilead Sci­ence’s remde­sivir. In vit­ro stud­ies showed that when OYA1 is dosed with remde­sivir both com­pounds are marked­ly more effec­tive inhibit­ing Ebo­la virus repli­ca­tion and do so at much low­er dos­es than is need­ed with either com­pound alone. OYA1 proved equal­ly effec­tive in stop­ping Ebo­la infec­tiv­i­ty when it was added at the time of infec­tion or 24 hours after an infec­tion.”

    The news just keeps get­ting bet­ter. Not only can Oya1 help com­bat COVID, but Ebo­la too. And when Oya1 and remde­sivir are com­bined, less of both is required, mak­ing it less like­ly drug-resis­tant strains will emerge:

    ...
    Dr. Harold Smith, founder and CEO of Oya­Gen said that: “The new­ly pub­lished find­ings are very encour­ag­ing and sug­gest that OYA1 may be a high­ly effec­tive treat­ment can­di­date for Ebo­la and Las­sa infec­tions. Oya­Gen’s lead drug can­di­date for Ebo­la may also improve the effi­ca­cy of remde­sivir in treat­ing Ebo­la infec­tions as com­bi­na­tion ther­a­py and there­by also may reduce the poten­tial emer­gence of drug resis­tant viral strains that are often seen when only one treat­ment modal­i­ty is used to com­bat infec­tious dis­eases.” “The pub­lished data are con­sis­tent with pri­or pub­lished stud­ies that show when OYA1 con­cen­tra­tions were high enough to sup­press cell growth in the lab, it slowed cell divi­sion (cyto­sta­t­ic) but did not kill the cells. These find­ings are con­sis­tent with human clin­i­cal tri­als that showed that the OYA1 is safe and well tol­er­at­ed in humans. We also not­ed that in com­par­ing the data report­ed in our pub­li­ca­tion to the clin­i­cal tri­al data from the 1960s that the amount of OYA1 antic­i­pat­ed to be required to inhib­it greater that 90% of virus repli­ca­tion appears to be at the low­er dos­es of drug than were giv­en to human sub­jects dur­ing the can­cer clin­i­cal tri­als.
    ...

    But that announce­ment by Oya­Gen under­sells the poten­tial impor­tance of this study. Because Oya1 (san­gi­vamycin) was­n’t just shown to be effec­tive against Ebo­la. It was shown to be effec­tive against a vari­ety of virus­es, includ­ing virus­es that don’t con­tain the pro­teins Oya1 is tar­get­ing, lead­ing researchers to con­clude that Oya1 might be a good can­di­date as a “broad-spec­trum” antivi­ral drug. This is the holy grail of emerg­ing infec­tious dis­eases:

    Virus­es
    2021, 13(1), 52; https://doi.org/10.3390/v13010052

    A Nov­el Ebo­la Virus VP40 Matrix Pro­tein-Based Screen­ing for Iden­ti­fi­ca­tion of Nov­el Can­di­date Med­ical Coun­ter­mea­sures
    by Ryan P. Bennett1,† Court­ney L. Finch2,† Ele­na N. Postnikova2, Ryan A. Stewart1, Yingyun Cai2, Shuiqing Yu2, Janie Liang2, Julie Dyall2, Jason D. Salter1, Harold C. Smith1,* and Jens H. Kuhn2,*

    1 Oya­Gen, Inc., 77 Ridge­land Road, Rochester, NY 14623, USA
    2 NIH/NIAID/DCR/Integrated Research Facil­i­ty at Fort Det­rick (IRF-Fred­er­ick), Fred­er­ick, MD 21702, USA

    Aca­d­e­m­ic Edi­tor: Shan-Lu Liu
    Received: 23 Decem­ber 2020 / Accept­ed: 29 Decem­ber 2020 / Pub­lished: 31 Decem­ber 2020

    Abstract

    Filovirus­es, such as Ebo­la virus and Mar­burg virus, are of sig­nif­i­cant human health con­cern. From 2013 to 2016, Ebo­la virus caused 11,323 fatal­i­ties in West­ern Africa. Since 2018, two Ebo­la virus dis­ease out­breaks in the Demo­c­ra­t­ic Repub­lic of the Con­go result­ed in 2354 fatal­i­ties. Although there is progress in med­ical coun­ter­mea­sure (MCM) devel­op­ment (in par­tic­u­lar, vac­cines and anti­body-based ther­a­peu­tics), the need for effi­ca­cious small-mol­e­cule ther­a­peu­tics remains unmet. Here we describe a nov­el high-through­put screen­ing assay to iden­ti­fy inhibitors of Ebo­la virus VP40 matrix pro­tein asso­ci­a­tion with viral par­ti­cle assem­bly sites on the inte­ri­or of the host cell plas­ma mem­brane. Using this assay, we screened near­ly 3000 small mol­e­cules and iden­ti­fied sev­er­al mol­e­cules with the desired inhibito­ry prop­er­ties. In sec­ondary assays, one iden­ti­fied com­pound, san­gi­vamycin, inhib­it­ed not only Ebo­la viral infec­tiv­i­ty but also that of oth­er virus­es. This find­ing indi­cates that it is pos­si­ble for this new VP40-based screen­ing method to iden­ti­fy high­ly potent MCMs against Ebo­la virus and its rel­a­tives.

    1. Intro­duc­tion

    Filovirus­es (Monone­gavi­rales: Filoviri­dae) have lin­ear non-seg­ment­ed neg­a­tive-sense RNA genomes (up to 19.1 kb), con­sist­ing of the canon­i­cal genes 3′-NP-VP35-VP40-GP-VP30-VP24‑L-5′ that encode nucle­o­pro­tein (NP), poly­merase cofac­tor (VP35), matrix pro­tein (VP40), spike gly­co­pro­tein (GP1,2), tran­scrip­tion­al acti­va­tor (VP30), RNA com­plex-asso­ci­at­ed pro­tein (VP24), and large pro­tein (L, includ­ing an RNA-direct­ed RNA poly­merase [RdRp] activ­i­ty), respec­tive­ly [1]. The fam­i­ly Filoviri­dae cur­rent­ly includes six gen­era, of which two, Ebolavirus and Mar­burgvirus, har­bor virus­es known to cause human dis­ease [2]. Based on fre­quen­cy and size of doc­u­ment­ed human filovirus dis­ease out­breaks, two ebolavirus­es (Ebo­la virus [EBOV] and Sudan virus [SUDV]) and one mar­burgvirus (Mar­burg virus [MARV]) are of the great­est pub­lic health con­cern [1]. EBOV, the eti­o­log­ic agent of Ebo­la virus dis­ease (EVD) [3], caused the two largest filovirus dis­ease out­breaks on record: 28,652 cas­es with 11,323 deaths were report­ed dur­ing the 2013–2016 EVD out­break in West­ern Africa; and 3481 cas­es with 2299 deaths occurred dur­ing a 2018–2020 EVD out­break in the Demo­c­ra­t­ic Repub­lic of the Con­go [4,5].

    Rel­a­tive­ly lit­tle progress has been made toward estab­lish­ing anti-filovirus med­ical coun­ter­mea­sures (MCMs) until recent­ly. The 2013–2016 EVD out­break in par­tic­u­lar sparked inno­va­tion, result­ing in the first Euro­pean- and US-approved EBOV vac­cines [6]. Addi­tion­al­ly, a ran­dom­ized con­trolled phase II/III tri­al (“PALM”) con­duct­ed dur­ing this out­break indi­cat­ed improved clin­i­cal out­comes in cer­tain patient cohorts receiv­ing mon­o­clon­al anti­body mAb114 or mon­o­clon­al anti­body cock­tail REGN-EB3 [7]. Remde­sivir, a nucle­o­side ana­log that was high­ly effi­ca­cious in non-human pri­mate mod­els of EVD [8], had lit­tle effect on patient out­come [7]. Thus, EVD patient ther­a­py has been lim­it­ed to the use of anti­bod­ies, which do not pen­e­trate immune-priv­i­leged sites (i.e., brain, eyes, pla­cen­ta, and testes) known to har­bor EBOV in some EVD sur­vivors [9] and which may result in the evo­lu­tion of EBOV escape mutants [10]. Small mol­e­cules may have logis­ti­cal advan­tages over anti­bod­ies with regard to long-term stor­age, trans­port to remote loca­tions, and patient admin­is­tra­tion and there­fore could be alter­na­tives to anti­bod­ies or could be part of com­bi­na­to­r­i­al ther­a­pies with anti­bod­ies [11].

    An ide­al filovi­ral ther­a­peu­tic is virus spe­cif­ic enough to min­i­mize off-tar­get effects but broad enough to tar­get mul­ti­ple aspects of a par­tic­u­lar step of the virus life cycle, mul­ti­ple steps of the virus life cycle, and/or sev­er­al close­ly relat­ed virus­es [12]. For instance, REGN-EB3 is a cock­tail of three mon­o­clon­al anti­bod­ies, all of which affect EBOV cell entry by tar­get­ing dis­tinct GP1,2 sites [13]. In the absence of ide­al ther­a­peu­tics, com­bi­na­tions of ther­a­peu­tics of dif­fer­ent class­es that, ide­al­ly, work syn­er­gis­ti­cal­ly may be con­sid­ered [14], although com­bi­na­to­r­i­al prod­ucts face more chal­leng­ing reg­u­la­to­ry hur­dles than sin­gle prod­ucts.

    Most small mol­e­cules that have proven high­ly effi­ca­cious in non-human pri­mate mod­els of EVD and/or have been eval­u­at­ed in clin­i­cal tri­als are nucle­o­side analogs (e.g., favipi­ravir [15,16,17] and remde­sivir [7]). Typ­i­cal­ly, these mol­e­cules are asso­ci­at­ed with a sin­gle mech­a­nism of action, i.e., the inhi­bi­tion of virus repli­ca­tion and/or tran­scrip­tion through inter­fer­ence with the L‑contained RdRp activ­i­ty [8,18,19].

    To nar­row the gap in cur­rent EVD ther­a­peu­tic avail­abil­i­ty, we sought to devel­op an assay to iden­ti­fy small mol­e­cules that tar­get steps of the EBOV life cycle oth­er than viri­on entry or replication/transcription. The last step in the EBOV repli­ca­tion cycle includes par­ti­cle assem­bly, ribonu­cle­o­pro­tein (RNP) com­plex pack­ag­ing, and viri­on release from the host cell mem­brane [1]. This process is medi­at­ed by EBOV matrix pro­tein VP40, a mul­ti­func­tion­al pro­tein [20,21]. The VP40 monomer con­sists of dis­tinct N‑terminal domains (NTDs) and C‑terminal domains (CTDs) that are joined through a flex­i­ble link­er [22]. NTD–NTD inter­ac­tions can lead to the for­ma­tion of cyclic octamers that remain in the cytosol and bind RNA for reg­u­la­tion of EBOV repli­ca­tion and tran­scrip­tion [20,22,23,24,25,26,27,28,29,30,31,32,33,34,35]. VP40 requires three cru­cial inter­ac­tions to pro­mote for­ma­tion of viral par­ti­cles (Fig­ure 1): VP40 must first form homod­imers via NTD–NTD inter­ac­tions for which residue L117 is cru­cial; such dimers accu­mu­late at the plas­ma mem­brane due to VP40 domain rearrange­ment by which the CTD is flipped away from the NTD. This rearrange­ment expos­es a basic patch com­prised of six lysine residues (221, 224, 225, 270, 274, and 275) that inter­act with the inner mem­brane. This CTD jux­ta­po­si­tion expos­es an addi­tion­al NTD sur­face con­tain­ing a con­served W95 that forms a sec­ondary NTD–NTD inter­ac­tion, which results in hexa­m­er­ic VP40 moi­eties. Inter­ac­tions among VP40 hexa­m­ers form the viral matrix [20]. VP40 alone under­goes these inter­ac­tions and there­by forms viri­on-like par­ti­cles (VLPs) that are secret­ed from pro­duc­er cells [20].

    Our assay focused on VP40 because it is absolute­ly required for EBOV par­ti­cle pro­duc­tion [25]. Addi­tion­al­ly, sin­gle and dou­ble mutants in the four dis­crete inter­ac­tions are known to com­plete­ly obstruct oligomer­iza­tion and VLP for­ma­tion [25]. Our hypoth­e­sis was that small-mol­e­cule dis­rup­tion of this cru­cial nucle­ation for high­er-order assem­bly of VP40 would inhib­it viri­on for­ma­tion [20,30]. There­fore, we designed a flu­o­res­cent live-cell assay based sole­ly on EBOV VP40 expres­sion to screen for com­pounds that could dis­rupt mem­brane for­ma­tion of VP40-based VLPs; this dis­rup­tion would direct­ly affect the abil­i­ty of VP40 to form VLPs on the cell sur­face and would be iden­ti­fied by the screen­ing.

    We iden­ti­fied a nucle­o­side ana­log, san­gi­vamycin, that inhib­it­ed both EBOV VP40 asso­ci­a­tion with the cell mem­brane and cel­lu­lar viri­on-like par­ti­cle release. As expect­ed from these results, san­gi­vamycin inhib­it­ed the repli­ca­tion of EBOV but, sur­pris­ing­ly, it also inhib­it­ed the repli­ca­tion of EBOV’s close rel­a­tive, MARV, as well as the unre­lat­ed Las­sa virus (LASV), cow­pox virus (CPXV), and vac­cinia virus (VACV), which do not express VP40 orthologs. Using an EBOV minigenome assay that does not encode or express VP40, we demon­strate that these broad-spec­trum effects are like­ly due to a high­ly effi­cient sec­ondary inter­ac­tion with RdRps or oth­er viral pro­teins required for viral repli­ca­tion and/or tran­scrip­tion. These data indi­cate that the VP40-based screen­ing is suit­able for the iden­ti­fi­ca­tion of nov­el EBOV MCMs and that san­gi­vamycin could poten­tial­ly be devel­oped as a broad-spec­trum antivi­ral once its mech­a­nism of action is fur­ther clar­i­fied.

    ...

    ———–

    “A Nov­el Ebo­la Virus VP40 Matrix Pro­tein-Based Screen­ing for Iden­ti­fi­ca­tion of Nov­el Can­di­date Med­ical Coun­ter­mea­sures” by Ryan P. Ben­nett, et al.; Virus­es; 12/31/2020

    “We iden­ti­fied a nucle­o­side ana­log, san­gi­vamycin, that inhib­it­ed both EBOV VP40 asso­ci­a­tion with the cell mem­brane and cel­lu­lar viri­on-like par­ti­cle release. As expect­ed from these results, san­gi­vamycin inhib­it­ed the repli­ca­tion of EBOV but, sur­pris­ing­ly, it also inhib­it­ed the repli­ca­tion of EBOV’s close rel­a­tive, MARV, as well as the unre­lat­ed Las­sa virus (LASV), cow­pox virus (CPXV), and vac­cinia virus (VACV), which do not express VP40 orthologs. Using an EBOV minigenome assay that does not encode or express VP40, we demon­strate that these broad-spec­trum effects are like­ly due to a high­ly effi­cient sec­ondary inter­ac­tion with RdRps or oth­er viral pro­teins required for viral repli­ca­tion and/or tran­scrip­tion. These data indi­cate that the VP40-based screen­ing is suit­able for the iden­ti­fi­ca­tion of nov­el EBOV MCMs and that san­gi­vamycin could poten­tial­ly be devel­oped as a broad-spec­trum antivi­ral once its mech­a­nism of action is fur­ther clar­i­fied.”

    Oya1 (san­gi­vamycin) could poten­tial­ly be devel­oped as a broad-spec­trum antivi­ral once its mech­a­nism of action is fur­ther clar­i­fied. It’s demon­strat­ed antivi­ral activ­i­ty was so potent that the researchers could­n’t explain how it was work­ing against many of these virus­es. That’s the gen­uine­ly extreme­ly excit­ing results just pub­lished by Oya­Gen in col­lab­o­ra­tion with NIH/NIAID/DCR/Integrated Research Facil­i­ty at Fort Det­rick. The top infec­tious dis­ease lab in the world is sign­ing off on these find­ings. And yet no one cares. Why is that?

    Posted by Pterrafractyl | January 15, 2021, 3:10 pm

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